Analysis of <i>MET </i>exon 14skippingmutations in non–small cell lung cancer (NSCLC) by histology and specific mutation.
Authors: Jennifer Aline Marks, Jun Yin, Balazs Halmos, Lyudmila Bazhenova, Suresh S. Ramalingam, Melina Elpi Marmarelis, Joanne Xiu, Phillip Walker, Matthew James Oberley, Patrick C. Ma, Stephen V. Liu
Journal: Journal of Clinical Oncology (2022)

9119 Background: MET exon 14 skipping mutations (METex14) join a growing list of viable therapeutic targets in advanced NSCLC. Several unique features distinguish METex14 from other established targets. METex14 has been characterized as a tumor-agnostic genomic alteration, though most frequently reported in lung adenocarcinoma. However, METex14 represents a family of mutations (mt), not a single alteration, and there is notable heterogeneity in histology. The degree and significance of heterogeneity within METex14 have not been well characterized. Methods: NSCLC tissue samples were analyzed with DNA-based next-generation sequencing (NGS; 592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-based whole transcriptome sequencing (WTS, NovaSeq), and immunohistochemistry (IHC) at Caris Life Sciences (Phoenix, AZ). PD-L1 expression utilized the 22C3 clone (Dako); TMB-high was defined as ≥ 10 mt/Mb. Wilcoxon or Fisher’s exact were used to determine statistical significance (p without and q with multi comparison correction). Immune cell fraction (QuanTiseq) and pathway analysis (ssGSEA) were informed by WTS analysis. Results: A total of 440 METex14 cases were identified: 49 (11.1%) with squamous histology, 381 (86.6%) with non-squamous histology, and 10 (0.2%) with adenosquamous histology. A total of 147 distinct METex14 mutations were detected. The most common METex14 mutations were D1028H (8.4%), D1028N (7.0%), c.3082+2T &gt; C (5.7%), D1028Y (5.2%), and c.3082+1G &gt; A (4.5%). Co-mutations in TP53 were common (43.9%) but varied by specific METex14 mutation; TP53 co-mutations were observed in 53.9% of c.3082+3A &gt; T but only 21.1% of c.3082+1G &gt; T. Among all METex14 cases, 8.6% were TMB-high, but this varied by specific mutation with a median TMB of 2 mt/Mb in MET c.3082+2T &gt; A and a median of 7 mt/Mb in MET c.3082+1G &gt; C (q &lt; 0.05). PD-L1 expression ≥ 1% was present in 82.2% of METex14 samples but also varied by specific METex14 mutation with a median PD-L1 tumor proportion score (TPS) of 97.5% in MET c.3082+1G &gt; C and a median TPS of 0% in MET c.3082+3A &gt; G (q &lt; 0.05). Co-mutations varied by histology: in squamous METex14, 90.4% had TP53 mt (p &lt; 0.001), 17.9% had KMT2D mt (p &lt; 0.05), and 10.7% had PIK3CA mt (p &lt; 0.05), while in non-squamous METex14, 60.7% had TP53 mt, 2.7% had KMT2D mt, and 4.3% had PIK3CA mt. Survival was numerically shorter in squamous METex14 NSCLC compared to non-squamous (HR 1.22, p = 0.47, mOS 336 vs.1106 days). Conclusions: There is significant heterogeneity within METex14 NSCLC with differences in co-mutations, TMB, and PD-L1 expression noted among different METex14 mutations. While METex14 is detected in both squamous and non-squamous NSCLC, there are differences in enrichment of oncogenic pathways. The clinical impact of these differences warrants further investigation.